Ca²⁺ Microdomains, Calcineurin and the Regulation of Gene Transcription

Ca²⁺ ions function as second messengers regulating many intracellular events, including neurotransmitter release, exocytosis, muscle contraction, metabolism and gene transcription. Cells of a multicellular organism express a variety of cell-surface receptors and channels that trigger an increase of the intracellular Ca²⁺ concentration upon stimulation. The elevated Ca²⁺ concentration is not uniformly distributed within the cytoplasm but is organized in subcellular microdomains with high and low concentrations of Ca²⁺ at different locations in the cell. Ca²⁺ ions are stored and released by intracellular organelles that change the concentration and distribution of Ca²⁺ ions. A major function of the rise in intracellular Ca²⁺ is the change of the genetic expression pattern of the cell via the activation of Ca²⁺-responsive transcription factors. It has been proposed that Ca²⁺-responsive transcription factors are differently affected by a rise in cytoplasmic versus nuclear Ca²⁺. Moreover, it has been suggested that the mode of entry determines whether an influx of Ca²⁺ leads to the stimulation of gene transcription. A rise in cytoplasmic Ca²⁺ induces an intracellular signaling cascade, involving the activation of the Ca²⁺/calmodulin-dependent protein phosphatase calcineurin and various protein kinases (protein kinase C, extracellular signal-regulated protein kinase, Ca²⁺/calmodulin-dependent protein kinases). In this review article, we discuss the concept of gene regulation via elevated Ca²⁺ concentration in the cytoplasm and the nucleus, the role of Ca²⁺ entry and the role of enzymes as signal transducers. We give particular emphasis to the regulation of gene transcription by calcineurin, linking protein dephosphorylation with Ca²⁺ signaling and gene expression.